PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway.
The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. ... The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397. In PTEN-mutated cancer cells, FAK phosphorylation was retained even in suspension after detachment from extracellular matrix, accompanied by enhanced PI 3-K association with FAK and sustained PI 3-K activity, PIP3 levels, and Akt phosphorylation; expression of exogenous PTEN suppressed all five properties. PTEN-mutated cells were resistant to apoptosis in suspension, but most of the cells entered apoptosis after expression of exogenous PTEN or wortmannin treatment. Moreover, overexpression of FAK in PTEN-transfected cells reversed the decreased FAK phosphorylation and PI 3-K activity, and it partially rescued PIP3 levels, Akt phosphorylation, and PTEN-induced apoptosis. Our results show that FAK Tyr397 is important in PTEN interactions with FAK, that PTEN regulates FAK phosphorylation and molecular associations after detachment from matrix, and that PTEN negatively regulates the extracellular matrix-dependent PI 3-K/Akt cell survival pathway in a process that can include FAK.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Cell Adhesion Molecules, Cell Survival, Enzyme Inhibitors, Extracellular Matrix, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Tumor Cells, Cultured, Tumor Suppressor Proteins, Tyrosine
1-Phosphatidylinositol 3-Kinase, Cell Adhesion Molecules, Cell Survival, Enzyme Inhibitors, Extracellular Matrix, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Tumor Cells, Cultured, Tumor Suppressor Proteins, Tyrosine
J. Biol. Chem.
Date: Jul. 16, 1999
PubMed ID: 10400703
View in: Pubmed Google Scholar
Download Curated Data For This Publication
9728
Switch View:
- Interactions 1